Hepatocellular carcinoma (HCC) accounts for 85%- 90% of all primary liver cancers and HCC is the sixth most common cancer worldwide. HCC is a highly aggressive cancer with poor prognosis; frequently it remains undiagnosed until late-stage. The incidence of HCC is rising both in the United States and worldwide. In the United States, this increase is in large part due to the growing prevalence of fatty liver disease that parallels the high rates of obesity and diabetes. Ectopic lipid deposition in liver is the initial step on a continuum of liver dysfunction that can lead to non-alcoholic steatosis. NASH and other chronic insults to hepatocyte function, such as occur in hepatitis and alcoholic cirrhosis, are major risk factors for HCC. A deeper understanding of the cellular and molecular pathogenesis of HCC is central to support new drug development, a dire need for the many patients with this aggressively lethal cancer. RIFL, also known as Angptl8, is a recently discovered novel member of the angiopoietin-like family of secreted proteins that shows high enrichment in human liver. RIFL levels in human circulation are increased in several metabolic diseases that are risk factors for HCC development. To date, RIFL function has only been examined in lipid metabolism, where it is a major regulator of serum triglyceride levels and adiposity. RIFL expression or actions in cancer are completely unexplored. RIFL expression is altered in HCC and signals that increase the risk of HCC upregulate RIFL levels in human hepatoma cells. Preliminary studies support the hypothesis that RIFL may regulate pro-tumorigenic phenotypes in HCC. RIFL may exert these actions either on its own or through its impact on the bioavailability of Angptl4, a major secreted regulator of multiple pro-tumorigenic processes in cancer growth and metastasis. In Aim 1, cell based and vivo xenograft models are utilized to define the impact of gain and loss of function of RIFL on cancer cell phenotype in HCC. In Aim 2, we determine the consequence of RIFL deletion in vivo on the development of the HCC risk factors of obesity, fatty liver and ER stress. In Aim 2 we also determine if the development and severity of HCC in the mouse MUP-uPA/hypernutrition model is ameliorated by RIFL deletion. If these studies illustrate a role for RIFL in HCC, they will add new information to the current understanding of the basic mechanisms underlying HCC. This would generate new research avenues relevant in HCC to be pursued in future lines of investigation that would contribute to our understanding of the pathophysiological impact of metabolic diseases such as dyslipidemia/obesity on cancer development and progression.